1. Field of the Invention
The present invention relates to formulations for delivery of pharmaceutical agents such as therapeutic proteins and peptides by non-invasive routes to patients and to processes for preparing the formulations.
2. Description of the Prior Art
Effective, convenient, and comfortable delivery of pharmaceuticals to patients (both human and animal) is an area of major concern for a number of drugs. Various forms of pharmaceutical compositions and carrier agents are continually being developed to enhance the effectiveness and timing of drug delivery. Issues such as compositional stability, patient convenience, and difficulty in fabrication (e.g., cost) often need to be considered as formulations and delivery methods are developed, thus complicating the developmental process.
A conventional mode of delivery for many drugs is by oral ingestion of pills or tablets that disintegrate into primary particles and release the drug for absorption into the patient""s bloodstream from the stomach and gastrointestinal (GI) tract. However, there are many proteins and peptides that, while effective 5 therapeutically, are not suitable for conventional modes of delivery such as oral delivery, as they are susceptible to enzymatic degradation, and the large size and hydrophobic nature of these therapeutic agents makes them ill-suited for absorption through the GI tract. Saliva and gastrointestinal enzymes tend to degrade or digest the pharmaceutical agents, rendering them ineffective. Examples of such agents include insulin, leuprolide, human growth hormones, and others.
Traditionally, proteins or peptides have been delivered by parenteral routes to overcome those difficulties and obtain a desirable bioavailability. However, parenteral delivery, e.g., by injection, causes great discomfort and significant 15 inconvenience to patients, and consequently results in poor patient compliance, especially when the therapy is intended for treating chronic diseases, such as diabetes. A noninvasive delivery route is thus in order so that proteins and peptides can be administered to patients to achieve a desired bioavailability without the pain and discomfort associated with parenteral delivery.
Efforts have been directed toward developing less invasive routes to administer proteins and peptides. For example, one approach involves encapsulating the protein in a microsphere so that the insulin is protected from degradation until it hits the targeted site (e.g., the intestines), at which point the microsphere decomposes to release the insulin. See, e.g., U.S. Pat. No. 4,925,673 to Steiner, xe2x80x9cDelivery Systems for Pharmacological Agents Encapsulated with Protenoidsxe2x80x9d issued May 15, 1990; U.S. Pat. No. 4,976,968 to Steiner, xe2x80x9cAnhydrous Delivery Systems for Pharmacological Agents,xe2x80x9d issued Dec. 11, 1990, and U.S. Pat. No. 5,503,852 to Steiner et al., xe2x80x9cMethod for Making Self-assembling Diketopiperazine Drug Delivery System,xe2x80x9d issued Apr. 2, 1996, all of which are incorporated herein by reference. Delivery systems using microparticles may be pH sensitive; that is, they rely upon changes in pH along the patient""s digestive tract to cause degradation of the microsphere and release the encapsulated pharmaceutical agent. Similarly, compounds useful in developing a pharmaceutical composition for pill delivery of such agents are disclosed in U.S. Pat. Nos. 5,990,166 and 5,989,539 to Leone-Bay et al. These delivery mechanisms have drawbacks in that, among other things, the pharmaceutical agents are not immediately released into the bloodstream as the microsphere (or pill) must first travel to the patient""s gastrointestinal tract, disintegrate into primary particles, and be digested.
Efforts have been made to develop formulations effective for more immediate delivery of proteins and peptides through the patient""s pulmonary system or respiratory tract via inhalation. For example, U.S. Pat. Nos. 5,952,008, 5,830,853, 5,518,998, and 5,506,203, each incorporated herein, issued to Backstrom et al., disclose preparations in the form of a dry powder that include insulin pulverized to a small ( less than 10 micron) size and an enhancer compound for inhalation delivery to the lower respiratory tract. Formulations for enhancing absorption through the nasal membranes are disclosed in various patents including U.S. Pat. No. 5,902,789 to Stoltz, U.S. Pat. No. 5,112,804 to Kowarski, U.S. Pat. No. 5,693,608 to Bechgaard, and U.S. Pat. No. 5,059,587 to Yamamoto et al. Many formulations designed to increase effectiveness in delivery to the pulmonary system include use of steroids or acids, such as carboxylic acids, furidic acid, amino acids, glycyrrhetinic acid, glycytrhizic acid, organic acids such as succinic acid, tartaric acid, and so forth, which may be disadvantageous to the patient""s overall well-being.
A recent aerosol formulation for delivery of proteins and peptides is disclosed in US Pat. No. 5,230,884 to Evans et al., xe2x80x9cAerosol Formulations Including Proteins and Peptides Solubilized in Reverse Micelles and Process for Making the Aerosol Formulationsxe2x80x9d (incorporated herein). The Evans ""884 patent discloses an aerosol formulation to deliver polypeptides and proteins to the pulmonary region. The ""884 patent discloses that reverse micelle systems were formed. The micelles were emulsified in the hydrophobic propellant phase in the presence of surfactants, and the therapeutic agent was dissolved in the aqueous core of the micelles. However, the ""884 patent acknowledges the extreme difficulty in preparing the reverse micelle system as disclosed in that patent, and additionally, the micelles were adapted for delivery via the pulmonary region.
There are adverse long-term health effects associated with inhalation delivery of pharmaceutical agents. Additionally, when the pharmaceutical agents are delivered by spraying in the mouth with breath-activated inhalation, much of the drug remains in the mouth and degrades, without being absorbed into the bloodstream. This reduces the bioavailability of the drug, increases the cost to the patient, causes local and systemic side effects such as ehrush, and requires administration of larger doses of drug to achieve the same effect.
As may be appreciated, those in the field of pharmaceuticals continue to search for new pharmaceutical compositions and methods of delivery that more effectively and immediately deliver pharmaceutical agents to a patient, while maximizing patient convenience and comfort, compositional stability, and minimizing the difficulties and costs of fabrication.
The present invention comprises a formulation for non-invasive delivery of pharmaceutical agents, particularly proteins and peptides, by absorption through a membrane at a targeted site. The formulation comprises a suspension of solid-phase dehydrated particles in a delivery medium, wherein the particles comprise the dehydration product of the pharmaceutical agent and at least one of a surfactant and permeation enhancer. The delivery medium preferably comprises a fluid such as a propellant for pressurized aerosol delivery of the formulation to the patient""s targeted site where the pharmaceutical agent is absorbed through the mucosa. According to one aspect of the invention, the pharmaceutical agent comprises insulin; the surfactant is selected from Span, Tween, Brij, and Pluronic surfactants; and the permeation enhancer is selected from sodium lauryl sulfate, sodium laurate, and derivatives thereof. Each dose of pharmaceutical agent may be administered with a delivery system including a container, a metering pump or valve fitted to the container, and an actuator, such that a single dose may be administered by actuating the metering pump or valve fitted to the container.
The present invention also comprises a process for preparing a formulation suitable for mucosal absorption at a targeted site comprising preparing a solution of pharmaceutical agent with buffer, to which is added surfactant and/or permeation enhancer; dehydrating the solution to obtain solid-phase particles; and suspending the particles in a delivery medium.